Method for treating autism

ABSTRACT

A method for treating autism comprising the step of administering an effective amount of a medicament characterized as a NMDA-receptor antagonist or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/559,651 filed Apr. 5, 2004, entitled “MEMANTINE AS A TREATMENTFOR AUTISM AND AS THERAPY FOR COGNITIVE DECLINE DUE TO EPILEPSY” whichis hereby incorporated herein by reference in its entirety, includingall references cited therein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates in general to a method for treating autismand, more particularly, to a method for treating autism viaadministering an effective amount of a NMDA-receptor antagonist or apharmaceutically acceptable salt thereof

2. Background Art

Autism is a complex developmental disability that interferes with, amongother things, the normal development of the brain in the areas of socialinteraction and communication skills. It typically appears during thefirst three years of life and is the result of a neurological disorderwhich affects the functioning of the brain. Typically, autistic childrenand adults have difficulties in verbal and non-verbal communication,social interactions, and leisure or play activities.

According to the Autism Society of America (hereinafter the “ASA”),autism is generally characterized as one of five disorders coming underthe umbrella of Pervasive Developmental Disorders (PDD), a category ofneurological disorders characterized by severe and pervasive impairmentin several areas of development, including social interaction andcommunications skills (DSM-IV-TR). The five disorders under PDD areAutistic Disorder, Asperger's Disorder, Childhood DisintegrativeDisorder (CDD), Rett's Disorder, and PDD-Not Otherwise Specified(PDD-NOS). Specific diagnostic criteria for each of these disorders canbe found in the Diagnostic & Statistical Manual of Mental Disorders(DSM-IV-TR) as distributed by the American Psychiatric Association(APA).

The most common of the Pervasive Developmental Disorders, autism affectsan estimated 1 in approximately 200 births. Indeed, as of 2003-2004, asmany as 1.5 million Americans are believed to have some form of autism.Such a number is on the rise inasmuch as, based on statistics from theU.S. Department of Education and other governmental agencies, autism isgrowing at a rate of 10-17 percent per year. At these rates, the ASAestimates that the prevalence of autism could easily reach 4 millionAmericans in the next decade.

The overall incidence of autism is, for the most part, globallyconsistent. Indeed, autism knows no racial, ethnic, or socialboundaries, and family income, lifestyle, and educational levels do notaffect the chance of autism's occurrence. However, it has been found tobe four times more prevalent in boys than girls.

Since being first described by Dr. Leo Kanner in 1943, the understandingof autism has grown tremendously. However, the general public, and evenmany professionals in the medical, educational, and vocational fields,remain unaware of the effects of the disability and how to mosteffectively work with individuals having the disability. For example,autistic individuals may exhibit both positive and negative responses totheir environment. Though some may find it surprising, many children andadults with autism may make eye contact, show affection, smile andlaugh, and demonstrate a variety of other emotions, although in varyingdegrees.

Although autism is defined by a certain set of behaviors, it is aspectrum disorder in that its symptoms and characteristics can bepresent in a wide variety of combinations, from mild to severe.Therefore, autistic children and adults can exhibit any combination ofthe behaviors in any degree of severity. Two individuals, both with thesame diagnosis, may have varying skills and display very differentactions.

Indeed, every person with autism is an individual, and like allindividuals, each has a unique personality and combination ofcharacteristics. Those only mildly affected may exhibit slight delays inlanguage or communication and may face greater challenges in socialinteractions. For example, one may have difficulty initiating and/ormaintaining a conversation. Communication by autistic children or adultsis often displayed as talking at others (for example, a monologue on afavorite subject that continues despite attempts by others to interjectcomments).

Autism requires those affected by it to process and respond toinformation in unique ways. At times, aggressive and/or self-injuriousbehavior may exist. The following traits, as identified by the ASA, mayalso be present in persons with autism: Insistence on sameness orresistance to change; Difficulty in expressing needs; (i.e. usesgestures or pointing instead of words); Repeating words or phrases inplace of normal, responsive language; Laughing, crying, showing distressfor reasons not apparent to others; Prefers to be alone or aloof manner;Tantrums; Difficulty in mixing with others; May not want to cuddle or becuddled; Little or no eye contact; Unresponsive to normal teachingmethods; Sustained odd play; Spins objects; Inappropriate attachments toobjects; Apparent over-sensitivity or under-sensitivity to pain; No realfears of danger; Noticeable physical over-activity or extremeunder-activity; Uneven gross/fine motor skills; and/or Not responsive toverbal cues (i.e. acts as if deaf although hearing tests in normalrange).

For most people, our senses help us to understand what we areexperiencing. For example, our senses of touch, smell, sound, and tastecollaborate to give us a full experience of eating a ripe apple: thefeel of the smooth skin as we pick it up, its sweet smell as we move itto our mouth, the crunch of the fruit being bitten into, and the juicesrunning down our face as we enjoy the bite. For individuals with autism,however, sensory integration problems are common. In particular, theirsenses may be either over- or under-active. The fuzz of a kiwi mayactually be experienced as painful; a sweet, fruity smell may cause agagging reflex. Some children or adults with autism are particularlysensitive to sound, so that even the most ordinary daily noises arepainful. Many professionals feel that some of the typical autismbehaviors are actually a result of sensory integration difficulties.

Although there is no known single known cause for autism, it isgenerally accepted that it is caused by abnormalities in brain structureor function. The shape and structure of the brain in autistic versusnon-autistic children show differences when brain scans are viewed.Currently the link between heredity, genetics and medical problems arebeing investigated by researchers, as well as a number of othertheories. The theory of a genetic basis of the disorder is supported bythe fact that, in many families, there appears to be a pattern of autismor related disabilities. While no one gene has been identified ascausing autism, researchers are searching for irregular segments ofgenetic code that autistic children may have inherited. Whileresearchers have not yet identified a single “trigger” that causesautism to develop, it also appears that some children are born with asusceptibility to autism.

Other researchers are investigating the possibility that under certainconditions, a cluster of unstable genes may interfere with braindevelopment resulting in autism. Still other researchers areinvestigating problems during pregnancy or delivery as well asenvironmental factors such as viral infections, metabolic imbalances,and exposure to environmental chemicals.

According to the ASA, autism tends to occur more frequently thanexpected among individuals who have certain medical conditions,including Fragile X syndrome, tuberous sclerosis, congenital rubellasyndrome, and untreated phenylketonuria (PKU). Some harmful substancesingested during pregnancy also have been associated with an increasedrisk of autism. Early in 2002, The Agency for Toxic Substances andDisease Registry (ATSDR) prepared a literature review of hazardouschemical exposures and autism and found no compelling evidence for anassociation; however, there was very limited research and more needs tobe done.

Whatever the cause, parents can rest assured that autism is not causedby bad parenting. Children with autism and PDD are either born with thedisorder or with the potential to develop it. No known psychologicalfactors in the development of the child have been shown to cause autism.Furthermore, autism is not a mental illness; autistic children are notunruly kids who choose not to behave.

Notwithstanding the foregoing, and to the best of Applicant's knowledge,there is no cure for autism. There are, however, a number ofmedications, developed for other conditions, which have been found to besomewhat helpful in treating a limited number of the symptoms andbehaviors frequently found in individuals with autism, such ashyperactivity, impulsivity, attention difficulties, and anxiety.Examples of medications used to treat symptoms associated with autisminclude: Serotonin re-uptake inhibitors (e.g. clomipramine (Anafranil),fluvoxamine (Luvox) and fluoxetine (Prozac)) which have been effectivein treating depression, obsessive-compulsive behaviors, and anxiety thatare sometimes present in autism. Studies have shown that they may reducethe frequency and intensity of repetitive behaviors, and may decreaseirritability, tantrums and aggressive behavior. Some children have shownimprovements in eye contact and responsiveness. Other drugs, such asElavil, Wellbutrin, Valium, Ativan and Xanax, require more studies to bedone but may have a role in reducing behavioral symptoms.

Over the past 35 years, the most widely studied psychopharmacologicagents in autism have been anti-psychotic medications. Originallydeveloped for treating schizophrenia, these drugs have been found todecrease hyperactivity, stereotypic behaviors, withdrawal and aggressionin autistic children. Four that have been approved by the FDA areclozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa) andquetiapine (Seroquel). However, only risperidone has been investigatedin a controlled study of adults with autism. Unfortunately, like theantidepressants, these drugs all have adverse side effects, including,but not limited to, sedation.

Stimulants, such as Ritalin, Adderall, and Dexedine, used to treathyperactivity in children with ADHD have also been prescribed forchildren with autism. Although few studies have been done, they mayincrease focus, and decrease impulsivity and hyperactivity in autism,particularly in higher-functioning children. Unfortunately, adversebehavioral side effects are often observed.

While many of the above-identified medications do appear to be somewhathelpful in treating a limited number of the symptoms and behaviorsfrequently found in individuals with autism, a wide variety of sideeffects are associated with such medications.

It has now been surprisingly discovered that administering an effectiveamount of a NMDA-receptor antagonist or a pharmaceutically acceptablesalt thereof appears to substantially improve frontal executivefunctions associated with autistic symptoms, including, but not limitedto, speech expression and decreased perseveration. Furthermore,administering such a NMDA-receptor antagonist or a pharmaceuticallyacceptable salt thereof has not been shown to cause side effectsassociated with medications previously used to treat the symptoms ofautism.

It is therefore an object of the present invention, to provide a methodfor treating autism via administering an effective amount of aNMDA-receptor antagonist or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating autismcomprising the step of administering an effective amount of a medicamentcharacterized as a NMDA-receptor antagonist or a pharmaceuticallyacceptable salt thereof.

In accordance with the present invention, the step of administering aneffective amount of a medicament can include the step of administeringan effective amount of a medicament represented by the followingchemical structure:

wherein X₁ comprises CH₂ or R₁₅; wherein R₁₋₁₅ are the same or differentand comprise H, an amino group, a primary amine, a secondary amine, atertiary amine, a quaternary ammonium group, a hydroxy group, a straightor branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl,alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containingapproximately 1 to approximately 50 carbon atom(s), a silyl or siloxylgroup containing approximately 1 to approximately 50 silicon atom(s),and combinations thereof.

Preferably, the step of administering an effective amount of amedicament includes the step of administering an effective amount of amedicament represented by the following chemical structure:

wherein R₁₋₃ are the same or different and comprise H, an amino group, aprimary amine, a secondary amine, a tertiary amine, a quaternaryammonium group, a hydroxy group, a straight or branched alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkenyl, alkynyl group containing approximately 1 toapproximately 50 carbon atom(s), a silyl or siloxyl group containingapproximately 1 to approximately 50 silicon atom(s), and combinationsthereof.

In yet another preferred embodiment of the present invention, the stepof administering an effective amount of a medicament includes the stepof administering an effective amount of a medicament represented by thefollowing chemical structure:

In accordance with the present invention, the step of administering aneffective amount of a medicament may include the step of administeringan effective amount of a medicament represented by the followingchemical structure:

In another preferred embodiment of the present invention, the step ofadministering an effective amount of a medicament includes the step ofadministering an effective amount of 1-amino-3,5-dimethyladamantanehydrochloride and pharmaceutically acceptable derivatives thereof.

Preferably, the step of administering an effective amount of medicamentincludes the step of administering the medicament in a concentrationranging from approximately 1 mg to approximately 100 mg per day.

In yet another preferred embodiment of the present invention, the stepof administering an effective amount of medicament includes the step ofadministering the medicament in a concentration ranging fromapproximately 5 mg to approximately 20 mg per day.

The present invention is also directed to a method for treating autismcomprising the step of administering an effective amount of a medicamentrepresented by the following chemical structure:

wherein X₁ comprises CH₂ or R₁₅; wherein R₁₋₁₅ are the same or differentand comprise H, an amino group, a primary amine, a secondary amine, atertiary amine, a quaternary ammonium group, a hydroxy group, a straightor branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl,alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containingapproximately 1 to approximately 50 carbon atom(s), a silyl or siloxylgroup containing approximately 1 to approximately 50 silicon atom(s),and combinations thereof, and wherein the step of administering themedicament includes the step of administering the medicament in aconcentration ranging from approximately 5 mg to approximately 20 mg perday.

The present invention is further directed to a method for treatingautism comprising the step of administering an effective amount of amedicament characterized as a NMDA-receptor antagonist or apharmaceutically acceptable salt thereof; wherein the step ofadministering an effective amount of a medicament includes the step ofadministering an effective amount of 1-amino-3,5-dimethyladamantanehydrochloride and pharmaceutically acceptable derivatives thereof; andwherein the step of administering an effective amount of medicamentincludes the step of administering the medicament in a concentrationranging from approximately 5 mg to approximately 20 mg per day.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible of embodiment in many differentforms, there will herein be described in detail several specificembodiments with the understanding that the present disclosure is to beconsidered as an exemplification of the principles of the invention andis not intended to limit the invention to the embodiments illustrated.

In accordance with the present invention, a method for treating autismis disclosed which comprises the step of administering an effectiveamount of a medicament characterized as a NMDA-receptor antagonist or apharmaceutically acceptable salt thereof. Preferably, the NMDA-receptorantagonist is a moderate affinity NMDA-receptor antagonist. It will beunderstood that regardless of its ordinary meaning the term “moderate”will be defined in accordance with the comprehensive teachings asdisclosed by Merz in its Brief Profile of Memantine available from theinternet at http://www.memantine.com/en/brief_profile/, which is herebyincorporated herein by reference in its entirety.

In one embodiment of the present invention, the medicament isrepresented by the following chemical structure:

wherein X₁ comprises CH₂ or R₁₅; wherein R₁₋₁₅ are the same or differentand comprise H, an amino group, a primary amine, a secondary amine, atertiary amine, a quaternary ammonium group, a hydroxy group, a straightor branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl,alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containingapproximately 1 to approximately 50 carbon atom(s), a silyl or siloxylgroup containing approximately 1 to approximately 50 silicon atom(s),and combinations thereof.

In a second embodiment of the present invention, the medicament isrepresented by the following chemical structure:

wherein R₁₋₃ are the same or different and comprise H, an amino group, aprimary amine, a secondary amine, a tertiary amine, a quaternaryammonium group, a hydroxy group, a straight or branched alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkenyl, alkynyl group containing approximately 1 toapproximately 50 carbon atom(s), a silyl or siloxyl group containingapproximately 1 to approximately 50 silicon atom(s), and combinationsthereof.

In a third embodiment of the present invention, the medicament isrepresented by the following chemical structure:

and may, specifically, comprise the hydrochloride salt provided hereinbelow represented by the following chemical structure:

For purposes of clarity, and in an attempt to eliminate any potentialambiguity associated with the nomenclature of the above-identifiedmedicament, it will be understood that the specific medicament providedherein above is defined as 1-amino-3,5-dimethyladamantane hydrochloride,which is commercially available from Merz under the trade nameMemantine.

It will be understood that an “effective amount” of one or moreabove-identified medicament(s) can be administered, via any one of anumber of conventional means, to an autistic patient/subject.Preferably, the effective dose ranges in concentration fromapproximately 1 milligram (mg) to approximately 100 mg per day, and morepreferably ranges in concentration from approximately 5 mg toapproximately 20 mg per day. However, the effective amount will varydepending upon the weight of the patient/subject.

In support of the present invention, an experiment was conducted toevaluate the use of Memantine in children and adolescents with autisticspectrum disorders (hereinafter referred to as “ASD”). Memantine, hasbeen found to improve cognitive function by reducing the neuronalsignal-to-noise ratio as one mechanism of action. A range of 2.5-10 mgper day of Memantine was applied as an open-label trial in children withASD. Clinical observations of global function in language and/orbehavior pattern were assessed.

Thirty patients, including 24 males and 6 females with an average age of8.92 years and meeting DSM-IV criteria for ASD, were treated withMemantine for greater than 8 weeks. The patients were evaluated using aglobal clinical improvement scale rating for improvement in language andbehaviors based on parental observation and clinical appearance.Improvements were rated as follows: moderate to significant, mild tomoderate, or no improvement. The therapy ranged from between 8 to 40weeks, with an average duration of therapy of 18 weeks and an averagedaily dosage of 8.1 mg.

After the thirty patients were treated for more than 2 months withMemantine, parents reported improvements in 26 of the 30 patients in oneor more categories: attention, motor planning, language function (bothreceptively and expressively), and self-stimulatory behaviors. Moderateto significant improvement occurred in 16 of the 26, with milderimprovement in 10 of the 26. No side effects were reported.

While further controlled studies in ASD with Memantine can be beneficialto follow up on these observations, Memantine appears to clearly improvefrontal executive functions, including better attention, improved speechexpression, and decreased perseveration.

The foregoing description merely explains and illustrates the inventionand the invention is not limited thereto except insofar as the appendedclaims are so limited, as those skilled in the art who have thedisclosure before them will be able to make modifications withoutdeparting the scope of the invention.

1. A method for treating autism, comprising the step of: administeringan effective amount of a medicament characterized as a NMDA-receptorantagonist or a pharmaceutically acceptable salt thereof.
 2. The methodaccording to claim 1, wherein the step of administering an effectiveamount of medicament includes the step of administering the medicamentin a concentration ranging from approximately 1 mg to approximately 100mg per day.
 3. The method according to claim 1, wherein the step ofadministering an effective amount of medicament includes the step ofadministering the medicament in a concentration ranging fromapproximately 5 mg to approximately 20 mg per day.
 4. The methodaccording to claim 1, wherein the step of administering an effectiveamount of a medicament includes the step of administering an effectiveamount of a medicament represented by the following chemical structure:

wherein X₁ comprises CH₂ or R₁₅; wherein R₁₋₁₅ are the same or differentand comprise H, an amino group, a primary amine, a secondary amine, atertiary amine, a quaternary ammonium group, a hydroxy group, a straightor branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl,alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containingapproximately 1 to approximately 50 carbon atom(s), a silyl or siloxylgroup containing approximately 1 to approximately 50 silicon atom(s),and combinations thereof.
 5. The method according to claim 4, whereinthe step of administering an effective amount of medicament includes thestep of administering the medicament in a concentration ranging fromapproximately 1 mg to approximately 100 mg per day.
 6. The methodaccording to claim 4, wherein the step of administering an effectiveamount of medicament includes the step of administering the medicamentin a concentration ranging from approximately 5 mg to approximately 20mg per day.
 7. The method according to claim 1, wherein the step ofadministering an effective amount of a medicament includes the step ofadministering an effective amount of a medicament represented by thefollowing chemical structure:

wherein R₁₋₃ are the same or different and comprise H, an amino group, aprimary amine, a secondary amine, a tertiary amine, a quaternaryammonium group, a hydroxy group, a straight or branched alkyl,cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl, alkaryl, aralkyl,alkoxy, alkenyl, alkynyl group containing approximately 1 toapproximately 50 carbon atom(s), a silyl or siloxyl group containingapproximately 1 to approximately 50 silicon atom(s), and combinationsthereof.
 8. The method according to claim 7, wherein the step ofadministering an effective amount of medicament includes the step ofadministering the medicament in a concentration ranging fromapproximately 1 mg to approximately 100 mg per day.
 9. The methodaccording to claim 7, wherein the step of administering an effectiveamount of medicament includes the step of administering the medicamentin a concentration ranging from approximately 5 mg to approximately 20mg per day.
 10. The method according to claim 1, wherein the step ofadministering an effective amount of a medicament includes the step ofadministering an effective amount of a medicament represented by thefollowing chemical structure:


11. The method according to claim 10, wherein the step of administeringan effective amount of medicament includes the step of administering themedicament in a concentration ranging from approximately 1 mg toapproximately 100 mg per day.
 12. The method according to claim 10,wherein the step of administering an effective amount of medicamentincludes the step of administering the medicament in a concentrationranging from approximately 5 mg to approximately 20 mg per day.
 13. Themethod according to claim 1, wherein the step of administering aneffective amount of a medicament includes the step of administering aneffective amount of a medicament represented by the following chemicalstructure:


14. The method according to claim 13, wherein the step of administeringan effective amount of medicament includes the step of administering themedicament in a concentration ranging from approximately 1 mg toapproximately 100 mg per day.
 15. The method according to claim 13,wherein the step of administering an effective amount of medicamentincludes the step of administering the medicament in a concentrationranging from approximately 5 mg to approximately 20 mg per day.
 16. Themethod according to claim 1, wherein the step of administering aneffective amount of a medicament includes the step of administering aneffective amount of 1-amino-3,5-dimethyladamantane hydrochloride andpharmaceutically acceptable derivatives thereof.
 17. The methodaccording to claim 16, wherein the step of administering an effectiveamount of medicament includes the step of administering the medicamentin a concentration ranging from approximately 1 mg to approximately 100mg per day.
 18. The method according to claim 16, wherein the step ofadministering an effective amount of medicament includes the step ofadministering the medicament in a concentration ranging fromapproximately 5 mg to approximately 20 mg per day.
 19. A method fortreating autism, comprising the step of: administering an effectiveamount of a medicament represented by the following chemical structure:

wherein X₁ comprises CH₂ or R₁₅; wherein R₁₋₁₅ are the same or differentand comprise H, an amino group, a primary amine, a secondary amine, atertiary amine, a quaternary ammonium group, a hydroxy group, a straightor branched alkyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aryl,alkaryl, aralkyl, alkoxy, alkenyl, alkynyl group containingapproximately 1 to approximately 50 carbon atom(s), a silyl or siloxylgroup containing approximately 1 to approximately 50 silicon atom(s),and combinations thereof; and wherein the step of administering themedicament includes the step of administering the medicament in aconcentration ranging from approximately 5 mg to approximately 20 mg perday.
 20. A method for treating autism, comprising the step of:administering an effective amount of a medicament characterized as aNMDA-receptor antagonist or a pharmaceutically acceptable salt thereof;wherein the step of administering an effective amount of a medicamentincludes the step of administering an effective amount of1-amino-3,5-dimethyladamantane hydrochloride and pharmaceuticallyacceptable derivatives thereof; and wherein the step of administering aneffective amount of medicament includes the step of administering themedicament in a concentration ranging from approximately 5 mg toapproximately 20 mg per day.